Yttrium-90-Ibritumomab Tiuxetan (Zevalin) Radioimmunotherapy After Cytoreduction With ESHAP Chemotherapy In Patients With Relapsed Follicular Non-Hodgkin’s Lymphoma (NHL): Interim Results Of a Phase II Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4404-4404 ◽  
Author(s):  
Soham D. Puvvada ◽  
Daniel O. Persky ◽  
Lora Inclan ◽  
Jonathan H. Schatz ◽  
Ellen M Chase ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Median Time ◽  
Residual Disease ◽  
Phase Ii Study ◽  
Time To Progression ◽  
Intent To Treat ◽  
Treat Analysis ◽  
Minimal Residual

Abstract Background Radioimmunoconjugates are effective treatment in relapsed/refractory follicular lymphoma (FL) when used as single agents, and can result in effective disease control (Kaminski et al, NEJM 1993; Witzig, JCO 2002). When used as consolidative treatment following a course of initial chemotherapy for patients with newly diagnosed FL, durable remissions have been noted (Gordon LI et al, Blood 2004). As a pure high energy beta emitting isotope, Zevalin has several advantages and has been well studied in relapsed refractory indolent NHL (Witzig TE et al, JCO 2002). Therefore, our hypothesis is that radioimmunoconjugates significantly change outcome for patients with FL when given in a situation of minimal residual disease, and number of long term remissions would increase with initial cytoreduction. For cytoreduction, we chose to use an outpatient formulation of ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin): ESHAP has excellent efficacy as a salvage regimen in treating relapsed low-grade lymphomas (Rodriguez-Monge EJ et al, Hem Oncol Clin N Am, 1997). Further, it is not utilized by community oncology practices fostering chemo sensitivity in a relapsed setting. Methods Histologically confirmed CD 20 + relapsed FL, ≥1< 4 prior therapies, age 18, ECOG performance status 0–2, measurable disease, signed informed consent, creatinine, bilirubin< 2.0 x ULN , platelet counts ≥150,000 able to receive 0.4 mCi/kg of Zevalin; patients with platelet counts 100,000-150,000 received 0.3mCi/kg dose of Zevalin. Patients were treated with 2 cycles of ESHAP every 28 days. At subsequent restaging, if bone marrow aspirate, biopsy showed<25% involved and expected biodistribution, Zevalin was administered. If Bone marrow involvement was >25 % was noted, patients were taken off study secondary to treatment failure. Results Twenty-eight patients with FL were enrolled with total 8 year follow-up. 6 patients did not complete the study: one patient was ineligible secondary to re-review of path showing DLBCL. Three patients were ineligible for study completion secondary to bone marrow showing residual involvement. Two patients withdrew secondary to toxicities: one from a perforated duodenal ulcer (SAE), and one from side effects of ESHAP chemotherapy including nausea, progressive functional decline. Other Grade 3, 4 adverse events included myelosuppression. Twenty-two patients were evaluable for response. Of the 22 evaluable patients, the overall response rate was 72% (17/22) with another 13 % achieving stable disease. After follow-up of 8 years, the median progression free survival (PFS) was 10 months for both the intent to treat analysis and responders (p=0.14). The median overall survival (OS) in the intent to treat analysis was 63 months, and the median OS in the 8 year follow-up of responders has not been reached (p=0.02). When analyzed by median number of prior therapies, the median PFS for patients with more than one prior chemotherapy regimen was 9, whereas the median PFS for patients with one prior regimen was 22 months. Similarly, for patients with more than one prior therapy, the median OS was 54 months, whereas the median OS for patients with one prior regimen has not been reached at 8 year follow-up. Conclusions In prior long term follow-up data(7 years) of a phase I/II study of Zevalin (Gordon et al, Blood 2004) in NHL including FL, the median time to progression in responders was 12.6 months, and durable responses were noted in 5/51 patients with FL. In a phase II study of relapsed FL treated with Zevalin (Witzig et al, JCO 2002) the median time to progression was 6.8 months, and in a subsequent Phase III study comparing Zevalin to rituximab, the median time to progression was 11.2 months. In comparison to above studies, our study has shown that outpatient ESHAP is an effective cytoreductive regimen. Zevalin is active when administered in a setting of minimal residual disease early in the disease course as evidence by the excellent overall survival of the responders. Disclosures: Off Label Use: Use of the investigational agent MLN8237 in combination in patients with aggressive B-cell NHL. Persky:Millennium: The Takeda Oncology Company: Research Funding.

Long-Term Complete Molecular Remissions in Untreated Symptomatic Follicular Lymphoma Treated with Rituximab as Single Agent and in Combination with Interferon-alpha-2a: Analysis of Minimal Residual Disease in the Randomized Phase II Study M39035.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1393-1393
Author(s):  
Jesper Jurlander ◽  
Christian Geisler ◽  
Hans Hagberg ◽  
Harald Holte ◽  
Tuula Lehtinen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Interferon Alpha ◽  
Phase Ii ◽  
Residual Disease ◽  
Phase Ii Study ◽  
First Year ◽  
Minimal Residual

Abstract From 9/98 to 11/99, 126 patients with symptomatic previously untreated or first relapse (&lt; 6 months of chlorambucil and/or local radiotherapy) CD20+ low-grade lymphoma, were included in a multicenter randomised phase II study. The treatment consisted of a first cycle of rituximab 375 mg/sqm q wk x 4. Pts in CR at week 14 were observed with no further treatment until symptomatic relapse, while pts with SD or PD went off study. Pts with PR or minor response were randomised to receive either a second cycle of rituximab 375 mg/sqm q wk x 4 or interferon-alpha-2a (IFN) 3 MIU/day sc (wk 1), 4,5 MIU/day (wk 2–5) in combination with rituximab 375 mg/sqm q wk (w 3–6). The clinical data from this study has previously been reported (Kimby E, et al. Ann Oncol2002;13 (Suppl 2):85). 38 patients (30%) fulfilled the criteria for CR, and were eligible for analysis of minimal residual disease (MRD). 14 more patients achieved CR at a time point later than first follow up after end of treatment. Per protocol, these patients are not included in the present analysis. By standard DNA-based PCR, presence of either a t(14;18) fusion transcript (MCR/mbr) or a clonal rearrangement of the Ig heavy chain (CDR3) could be detected in the diagnostic bone marrow and blood sample from 23 patients. These patients have now been studied for MRD, with a median follow-up time of 62 months. In dilution experiments the sensitivity of the assays was between 1:10−3 and 1:10−4. A given sample was considered negative if the PCR reaction was negative in three independent experiments, using up to 2 μg of template DNA. Patients were tested in blood and bone marrow at 10–16 weeks, 38–40 weeks and 52 weeks following treatment. A total of 175 samples, including 49 samples from patients in continued CR up to 5 years after treatment, have been analysed. Of 72 paired blood and bone marrow samples, only three showed inconsistency between blood and bone marrow, all three being positive in bone marrow and negative in blood. The frequency of MRD negativity 10–16 weeks after treatment was 4/9 (44%) in patients who received 1 cycle of rituximab, 3/5 (66%) in patients who received two cycles of rituximab and 7/9 (77%) in patients who received two cycles of rituximab with IFN priming. This trend towards a dose-response relation was however not significant, due to the small number of patients in each treatment group. The median duration of CR in patients who were negative at all three timepoints during the first year (n=14) was 62 months, compared to 21 months in patients (n=9) with one or more positive samples (p&lt;0,005). At a median follow up of 62 months 9/14 patients who were MRD negative through the first year remain in complete molecular remission, compared to 1/9 patients who had one or more positive blood or bone marrow samples during the first year (p&lt;0,03). Thus, sustained long-term complete molecular remissions are achievable with rituximab alone or in combination with IFN, and predictable by MRD status during the first year post treatment. Whether the quality of response is related to the dose of rituximab or the combination with IFN, and whether the response can be predicted using blood samples alone, must await the results of the ongoing ML16865 randomised phase III trial of rituximab vs IFN/rituximab in the same group of patients.

Minimal Residual Disease and Normalization of the Bone Marrow after Long-Term Treatment with Alpha-Interferon2b in Polycythemia Vera. A Report on Seven Patients in Sustained Complete Hematological Remission with Major Molecular Responses.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1744-1744 ◽  
Author(s):  
Thomas Stauffer Larsen ◽  
Michael Boe Møller ◽  
Karin de Stricker ◽  
Peter Nørgaard ◽  
Jan Samuelsson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Term Treatment ◽  
Alpha Interferon ◽  
Molecular Response ◽  
Molecular Responses ◽  
Long Term Treatment ◽  
Minimal Residual

Abstract Background : Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by the presence of the JAK2V617 mutation in virtually all patients. Recently several studies have shown that the JAK2V617F mutational load decreases during treatment with alpha-interferon2 (1–6). Aim: To report on molecular and histomorphological bone marrow responses in seven PV patients with complete molecular remissions during and after long-term treatment with alpha-interferon 2b. Patients: Seven patients treated with alpha-interferon2b for a median of 84 months (range 31–120) are reported. In four of the patients alpha-interferon2b was started at the time of diagnosis and in three patients 9, 36 and 42 months from the time of diagnosis, respectively. Methods: The mutation was determined by allele specific PCR (n=2 only) (7) and quantitative PCR (qPCR) (n=5) (8). In three out of these patients qPCR JAK2V617F was performed on archived bone marrow from diagnosis (2 patients) and on peripheral blood (one patient) prior to treatment with alpha-interferon2b. A complete molecular remission (CMoR) was defined by less than 2 % JAK2 V617F mutated alleles (7). Results: Molecular Responses. All patients obtained a CMoR after a median of 84 months (29–120 months) of treatment with alpha-interferon2b. Subsequently all patients have discontinued alpha-interferon with a follow-up period of median 10 months (range 4–30 months) and sustained complete hematological remission. Furthermore, in three patients molecular responses have recently been updated – April and May 2008 - showing CMoRs in all (1,2 %, 0,9 % 0,1 % mutated alleles, respectively). Bone Marrow Responses. Follow-up bone marrow biopsies were available in five patients. Complete normalization of the bone marrow was seen in three patients after treatment with alpha-interferon2b for 84, 132 and 132 months, respectively. In the bone marrow from the patient being treated with alpha-interferon for 132 months a qPCR JAK2V617 analysis was performed detecting the mutation at a very low level (0,5 % mutated alleles). In two other patients, being treated with alpha-interferon2b for 24 and 120 months, respectively, and having obtained a CmoR in peripheral blood the bone marrow histomorphology showed marked regression of PV-features but in both patients still with focal areas displaying an increased number of morphologically abnormal megakaryocytes. Updated histomorphological and molecular response patterns will be presented. Discussion and Conclusion : Previous studies on the molecular response during alpha-interferon2a treatment have shown that a substantial proportion of patients achieve a significant molecular response after 12 months with a continuous decrease in the JAK2V617F mutation load at 24 and 36 months (1,5,6). This report confirms and extends preliminary data, showing that long-term treatment with alpha-interferon 2b in a subgroup of PV-patients is able to induce complete molecular remissions with normalization of the bone marrow morphology, which may even be sustained after discontinuation of alpha-interferon2b for up to 20 months (5). Prolonged treatment for several years seems necessary to induce such sustained responses, since treatment for only a few months has been reported to be followed by rapid recurrence of clonal hematopoiesis (9). In conclusion, a state of “minimal residual disease” may be achieved in PV by long-term immune therapy using alpha-interferon 2. Our observations call for large prospective clinical studies in which treatment with alpha-interferon is initiated up-front in patients with JAK2-positive PV and allied diseases. These studies should also aim at exploring the minimal dose of alpha-interferon needed to elicit complete molecular responses in order to minimize side effects of the drug and accordingly diminish the high drop-out rates reported in most previous studies.

scholarly journals Serial Minimal Residual Disease Evaluation in Patients with Chronic Lymphocytic Leukemia Under Long-Term Venetoclax Treatment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1876-1876
Author(s):  
Thomas Lew ◽  
Mary Ann Anderson ◽  
Constantine S. Tam ◽  
Sasanka Handunnetti ◽  
Dennis Carney ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Minimal Residual

Abstract Background The selective BCL2 inhibitor venetoclax (Ven) achieves an overall response rate of approximately 75-80% as a single agent in relapsed and refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL)1. At one year ~75% of patients (pts) are progression-free at the approved monotherapy dose of 400 mg/day1,2 and Ven is the only novel agent with a significant rate of minimal residual disease (MRD) negativity (MRD-neg)3. The temporal pattern of MRD levels and systematic long term follow up of pts stratified by their MRD status on Ven have not been reported. We report the long term outcomes according to MRD status for 59 pts with RR-CLL/SLL who attained objective disease response to Ven, and the temporal patterns of change in MRD. Methods We reviewed the clinical outcomes to July 2018 of 67 pts with RR-CLL/SLL enrolled since June 2011 on early phase clinical studies of Ven at our two hospitals. Analysis was restricted to the 59 pts who achieved a partial response or complete response by iwCLL criteria. Pts initially received 150-1200mg Ven/day (45 ≥400mg/day) on one of three ongoing trials: Phase 1 Ven monotherapy (NCT01328626) (n=36), Phase 1b Ven plus rituximab (NCT01682616) (n=14), or Phase 2 Ven monotherapy in del(17p) CLL/SLL (NCT01889186) (n=9). For this analysis MRD-negativity was defined as <1 cell in 10-4 leukocytes by ERIC criteria, or no cells with a CLL phenotype when <400,000 cells were analyzed in an assay with a minimum sensitivity of 0.1%. Of those pts reported as MRD-neg this was confirmed at a level of 10-4 in 71%4. Unless otherwise specified, MRD-neg refers to status in the bone marrow (BM) and pts who were not tested were considered to be MRD-pos (n=2 pts). Landmark analyses of time to progression (TTP) by MRD status used the median time to achievement of MRD-neg. Fisher exact test was used to assess the association of clinical, biological and treatment variables with achievement of MRD-neg. TTP and time to MRD-neg were estimated using the method of Kaplan-Meier, and comparisons among groups used the log-rank (Mantel-Cox) test. Results Of the 59 pts who achieved an objective response to Ven, 21 (36%) achieved MRD-neg in the BM and 26 (44%) in the PB. Of the 38 pts who did not achieve BM MRD-neg, 36 (95%) had at least one BM assessment on treatment; the two remaining pts did not clear MRD in the PB. The strongest positive predictor for the achievement of BM MRD-neg was treatment with Ven plus rituximab (9 of 14 [64%]) achieved vs 13 of 45 [27%] on Ven monotherapy (p=0.02)). Complex karyotype was a negative predictor in pts receiving ≥400mg/day. TP53 aberrant state (mutation and/or del(17p)), bulky adenopathy >5cm and fludarabine-refractoriness were not significantly associated with achievement of MRD-neg, irrespective of dose (table 1). The median time to MRD-neg was 8.2 (range 2 - 46) mths for BM (fig 1A) and 5 (range <1 - 50) mths for PB, with 22/26 (85%) pts who achieved PB MRD-neg doing so within 12 mths of starting Ven. 25/26 had a contemporaneous or subsequent BM aspirate and 20 (80%) achieved BM MRD-neg after a median of 3 (<1 - 17) further mths. After a median follow up of 25 (range 2 - 55) mths since attainment of BM MRD-neg, 8/21 (38%) pts have developed confirmed re-emergence of BM MRD, and a further 2 pts have re-developed PB MRD-pos. Median time to reemergence of BM MRD has not been reached (59% BM MRD relapse free at 2 years post attainment). In a landmark analysis from median time to BM MRD-neg (8.2 mths), TTP by iwCLL criteria was significantly longer among BM MRD-neg pts (n = 21; median TTP 65 mths [95% CI 47 - undefined]) than BM MRD-pos pts (n = 31; median 22 mths [95% CI 14 - 39]; Hazard Ratio (HR) 0.11; p<0.0001) (figure 1B). Similar patterns held for the equivalent landmark analysis according to PB MRD (HR 0.21; p = 0.0002). Conclusions Venetoclax frequently induces BM MRD-neg, and pts achieving BM MRD-neg have very durable responses. Combined Ven plus rituximab increases the rate of BM MRD-neg. With Ven therapy, PB MRD status appears to be a reasonable surrogate for BM MRD status, but further validation is required. Achievement of BM MRD-neg should be the aim of therapy with Ven and Ven-based combination approaches may be the most effective way to achieve this.Roberts; N Engl J Med; 2016;374:311-22.Stilgenbauer; Lancet Oncol; 2016;17:768-78.Seymour; Lancet Oncol; 2017;18:230-40.Rawstron; Leukemia; 2016;30:929-36. Disclosures Lew: Walter and Eliza Hall: Employment, Patents & Royalties. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria, Travel funding; Gilead: Honoraria; Pharmacyclics: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria. Roberts:AbbVie: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; Genentech: Research Funding; Janssen: Research Funding. Seymour:Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding.

scholarly journals Long Term Follow-up of a Phase II Study of Cladribine with Concurrent Rituximab in Patients with Hairy Cell Leukemia Variant

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1536-1536
Author(s):  
Dai Chihara ◽  
Evgeny Arons ◽  
Maryalice Stetler-Stevenson ◽  
Constance M. Yuan ◽  
Hao-Wei Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analog ◽  
Minimal Residual

Background Hairy cell leukemia (HCL) variant (HCLv) is considered a separate, more aggressive entity compared to classic HCL. HCLv responds poorly to single-agent purine analog with complete response (CR) rates below 10% and overall response rates under 50%. Rituximab combined with purine-analog can improve response rate and duration, but long-term data have not been reported for HCLv, particularly regarding minimal residual disease (MRD). We therefore update the results of a phase II trial with cladribine and concurrent rituximab in patients with HCLv, previously reported for 10 of the 20 patients enrolled. Methods Patients with HCLv with 0 to 1 prior courses of cladribine, and/or 0-1 prior courses of rituximab, received cladribine (0.15 mg/kg days 1-5), with 8 weekly doses of rituximab (375 mg/m2) beginning day 1. The primary endpoint was to determine CR rate and secondary endpoints included evaluating minimal residual disease (MRD) by blood and bone marrow aspirate flow cytometry, and bone marrow biopsy immunohistochemistry. Patients were able to receive a 2nd course of rituximab ≥ 6 months after the first, if and when MRD was detected in blood. Results Twenty patients were enrolled. Median age was 67 (range: 42-86) years. No patients had prior concurrent cladribine-rituximab. Eight were previously untreated, 1 had only splenectomy, 6 had prior cladribine, 1 had prior cladribine and splenectomy, 1 had prior rituximab, 1 had prior rituximab and splenectomy, 1 had cladribine, rituximab, and splenectomy, and 1 had combination rituximab-containing chemotherapy followed by cladribine. Out of 20 patients receiving concurrent cladribine-rituximab (CDAR), the CR rate was 95% (95% CI: 75-100%). This CR rate was superior to a historical control group of 3 of 39 HCLv patients who achieved CR to cladribine alone (p&lt;0.0001). Sixteen (80%, 95% CI: 56-94%) of 20 patients became MRD-free at 6 months; median duration of MRD-free CR was 72.0 months, with 9 of 16 still MRD-free at 5-108 (median 29.1) months. With median potential follow up of 88 months (range: 7-123 months), 10 patients received delayed rituximab and 4 re-achieved MRD-free CR. Six patients required alternative treatment and 6 patients died, 5 with HCLv including 1 with HCLv limiting treatment for lung cancer, and 1 with Parkinson's disease but still MRD-free. Time from progression of HCLv to death was 5.9-30.0 (median 28.1) months. Achieving MRD-free CR by 6 months after CDAR (16 vs 4 patients) was important for median progression free survival [PFS, unreached vs 17.4 mo, hazard ratio (HR) 0.031, 95% CI 0.003-0.29, p&lt;0.0001] and overall survival (OS, unreached vs 38.2 months, HR infinite since all 4 MRD+ deaths were prior to deaths of 2 patients who achieved MRD-free CR, p&lt;0.0001). A significant relationship between prior purine analog therapy or unmutated IGHV4-34 (n=7) status and either PFS or OS has not yet been observed. Conclusion Concurrent cladribine with rituximab is highly effective in HCLv irrespective of prior purine-analog treatment or IGHV4-34 status and should replace purine analog monotherapy as treatment. Patients with long-term MRD-free CR are being followed to determine whether concurrent cladribine-rituximab as 1st-3rd line systemic therapy can permanently eradicate HCLv. Patients who progress have limited OS. This provides a rationale for the testing of higher intensity approaches up front and the identification of additional treatment options for HCLv. Disclosures Kreitman: Genentech: Research Funding. OffLabel Disclosure: Rituximab for hairy cell leukemia

scholarly journals Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up

Blood ◽  
2018 ◽  
Vol 131 (21) ◽  
pp. 2331-2334 ◽  
Author(s):  
Robert J. Kreitman ◽  
Martin S. Tallman ◽  
Tadeusz Robak ◽  
Steven Coutre ◽  
Wyndham H. Wilson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Aspirate ◽  
Phase 1 ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Key Points ◽  
Long Term Follow Up ◽  
Minimal Residual

Key Points Moxetumomab pasudotox eradicated HCL MRD in >50% of CRs, even by the most sensitive measure, bone marrow aspirate flow cytometry. Elimination of MRD was significantly associated with prolonged CR duration.

scholarly journals Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1556-1560 ◽  
Author(s):  
S Wheaton ◽  
MS Tallman ◽  
D Hakimian ◽  
L Peterson
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hematoxylin And Eosin ◽  
Anti Cd20 ◽  
Minimal Residual

Minimal residual disease (MRD) can be detected in bone marrow core biopsies of patients with hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) using immunohistochemical (IHC) techniques. The purpose of this study was to determine whether the presence of MRD predicts bone marrow relapse. We studied paraffin- embedded bone marrow core biopsies from 39 patients with HCL in complete remission (CR) 3 months after a single cycle of 2-CdA. Biopsies performed 3 months posttherapy and annually thereafter were examined by routine hematoxylin and eosin (H&E) staining and IHC using the monoclonal antibodies (MoAbs) anti-CD45RO, anti-CD20, and DBA.44. At 3 months after therapy, 5 of 39 (13%) patients had MRD detectable by IHC that was not evident by routine H&E staining. Two of the five patients (40%) with MRD at 3 months have relapsed, whereas only 2 of 27 (7%) patients with no MRD and at least 1 year of follow up relapsed (P = .11). Over the 3-year follow-up period, two additional patients developed MRD. Overall, three of six (50%) patients with MRD detected at any time after therapy have relapsed, whereas only 1 of 25 (4%) patients without MRD has relapsed (P = .016). These data suggest that the presence of MRD after treatment with 2-CdA may predict relapse.

Molecular Long-Term Surveillance of CML Patients on Imatinib Therapy. Follow-Up of German Patients Treated within the IRIS Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1003-1003
Author(s):  
Martin C. Mueller ◽  
P. Paschka ◽  
T. Lahaye ◽  
Ch. Lorentz ◽  
N. Gattermann ◽  
...  
Keyword(s):  
Median Time ◽  
Nested Pcr ◽  
Residual Disease ◽  
Response To Therapy ◽  
Imatinib Therapy ◽  
Interferon Α ◽  
Tyrosine Kinase Domain ◽  
Molecular Response

Abstract High rates of complete cytogenetic response (CCR), the availability of sensitive methods to detect residual disease, and direct therapeutic consequences are leading motives to integrate regular molecular monitoring into the standards for the management of patients (pts) with chronic myeloid leukemia (CML). We sought to determine long-term dynamics of BCR-ABL mRNA expression levels in 132 CML pts (75 m, 57 f, median age 51, range 20–71 yrs) recruited into the IRIS study in 17 German centers. Pts were randomized to receive imatinib (n=69) or interferon α+Ara-C (IFN, n=63). Due to intolerance or lack of response 41 pts crossed over from IFN to imatinib. Response to therapy was sequentially monitored by conventional cytogenetics from bone marrow metaphases (n=806). BCR-ABL transcripts were determined in 1414 peripheral blood samples by quantitative real time RT-PCR (RQ-PCR) using the LightCycler technology. In case of low level (&lt;10 transcripts/2μl cDNA) or neg RQ-PCR, nested PCR was performed. Total ABL transcripts were quantified as internal controls. A single series of BCR-ABL plasmid dilutions served as standard for both BCR-ABL and ABL transcripts. In pts on 1st-line imatinib therapy median ratios BCR-ABL/ABL gradually decreased: 4.8% at mo 3, 0.88% at mo 6, 0.22% at mo 12, 0.17% at mo 18, 0.058% at mo 24, 0.066% at mo 30, and 0.023% at mo 36. After crossover to imatinib results were not significantly different: 15.5% at mo 3, 1.6% at mo 6, 0.28% at mo 12, 0.068% at mo 18, 0.045% at mo 24, and 0.041% at mo 30. After a median follow-up of 40 mo (1–47) 31/69 pts (45%) on 1st-line imatinib were still RQ-PCR pos, 20 pts (29%) were RQ-PCR neg and nested PCR pos, and in 4 pts (5.8%) BCR-ABL became undetectable by RQ- and nested PCR. After a median time of 25 mo (3–43) on 2nd-line imatinib therapy 19/41 pts (46%) were RQ-PCR pos, 9 pts (22%) were RQ-PCR neg and nested PCR pos, and in 5 pts (12%) BCR-ABL was undetectable by RQ- and nested PCR. Considering adequate RNA quality BCR-ABL became repeatedly undetectable in 4 pts after 18–33 mo of 1st-line imatinib therapy and in 5 pts 9–33 mo after crossover from IFN to imatinib. In one patient, BCR-ABL remained undetectable after a treatment free interval of 4 weeks. After achieving CCR, 5 pts (7.2%) on 1st-line and 2 pts (4.9%) on 2nd-line imatinib therapy experienced cytogenetic relapse after a median time of 10 mo (4–21). In none of these pts mutations of the tyrosine kinase domain of BCR-ABL were detected. BCR-ABL/ABL ratios after 12 mo of imatinib therapy were significantly lower in pts in continuous CCR vs pts with subsequent relapse (0.18 vs 0.60%, respectively, p=0.04). None of the relapsing patients had achieved a ratio BCR-ABL/ABL &lt;0.12% after 12 mo, which represents a 3-log reduction from baseline. During total follow-up ratios BCR-ABL/ABL &lt;0.12% have been achieved in 51 pts (74%) on 1st-line and in 21 pts (51%) on 2nd-line imatinib therapy. We conclude that (i) treatment with imatinib in newly diagnosed CML pts is associated with a rapid and steady decrease of BCR-ABL transcript levels, (ii) a short trial of IFN does not jeopardize molecular response to subsequent imatinib therapy, (iii) an increasing minority of pts achieve complete molecular remission, and (iv) ratios of BCR-ABL/ABL &lt;0.12% after 12 mo of therapy predict for long-term response.

Determination of Minimal Residual Disease in Patients with Acute Myeloid Leukemia by Multiparameter Flow Cytometry: Prognostic Impact at Different Checkpoints.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 400-400 ◽  
Author(s):  
Wolfgang Kern ◽  
Daniela Voskova ◽  
Claudia Schoch ◽  
Wolfgang Hiddemann ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Prognostic Impact ◽  
Minimal Residual ◽  
Marrow Cells

Abstract Guiding antileukemic treatment in patients with acute myeloid leukemia (AML) is increasingly based on levels of minimal residual disease (MRD) which can be quantified with high sensitivity by multiparameter flow cytometry (MFC). The optimum checkpoint for determination of MRD during the course of therapy, however, has not yet been determined. We applied MFC using a comprehensive panel of antibodies to identify leukemia-associated aberrant immunophenotypes (LAIPs) at diagnosis and to quantify MRD by individually selected antibody combinations. The prognostic impact of MRD levels was assessed in comparison to cytogenetics and age. Patients received double induction, consolidation, and maintenance therapies and underwent allogeneic stem cell transplantation if they were younger than 60 years and had a matched related donor. In 286 patients with newly diagnosed and untreated AML MFC-based assessment for the presence of LAIP has been performed. The median percentage of LAIP-positive bone marrow cells at diagnosis was 16.04% (range, 2.54%–76.14%). All individual LAIPs were applied to 26 normal bone marrow samples to estimate sensitivity based on the median percentages of LAIP-positive normal bone marrow cells which ranged from 0.00% to 1.01% (median, 0.02%). A total of 550 follow-up samples has been analyzed in these patients at different checkpoints (CP1, up to day 21 after start of therapy, n=85; CP2, day 22–60, n=122; CP3, day 61–120, n=158; CP4, day 121–365, n=137; CP5, after day 365, n=48). In order to adjust for differences in the percentages of LAIP-positive bone marrow cells at diagnosis the logarithmic difference (LD) between diagnosis and follow-up was calculated for each follow-up sample. The median LDs at the respective checkpoints were: CP1, 2.02; CP2, 2.29; CP3, 2.39; CP4, 2.53; and CP5, 2.81. Separation of patients according to the respective median LDs resulted in differences in event-free survival (EFS; CP1: 21.1 vs. 9.1 months, p=0.0711; CP2: 14.2 vs. 9.3 months, p=0.0095; CP3: 30.9 vs. 13.5 months, p=0.0055; CP4: median not reached vs. 14.1 months, p<0.0001; CP5: median not reached vs. 22.5 months, p=0.0001) and overall survival (OS; CP3: median not reached vs. 21.6 months, p=0.0332; CP4: 90% vs. 53% at 2 years, p=0.0058). Cox analysis using the LDs at the different checkpoints as continuous variables confirmed the prognostic impact on EFS (CP2, p=0.002; CP3, p=0.0003; CP4, p<0.0001; CP5, p<0.0001) and revealed an impact also on OS (CP3, p=0.003; CP4, p=0.001; CP5, p=0.029). Cox regression analysis taking into consideration cytogenetics and age as covariates proved the independent prognostic impact of LD at checkpoints 2 to 5 on both EFS and OS with the exception of LD at checkpoint 2 and OS. In fact, LD at checkpoint 5 was the only parameter independently related to EFS and OS. These data suggest that quantification of MRD by MFC in AML results in powerful and independent prognostic parameters. In particular during the first year of treatment MRD levels provide important prognostic information. Clincal trials should use MRD-based stratification in order to assess the efficacy of early treatment intensification in high-risk AML patients.

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