Long-term Molecular Remissions Research Articles

Fifteen-year remission in a patient with follicular lymphoma after high-dose chemotherapy with autologous stem cell transplantation as a first-line treatment

We present a description of a clinical case of the use of high-dose therapy with autologous stem cell transplantation in the first line of therapy in a patient with FL

Follow-up of Chronic Myeloid Leukemia Patients whose Tyrosine Kinase Treatment Was Stopped: Case Series

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the formation of the BCR ABL1 fusion protein with translocation t(9;22) (Philadelphia chromosome-Ph). With recent studies, it has been understood that the treatment of adult chronic phase CML patients who have achieved a deep molecular response with the use of TKI and can maintain this response for a long time can be safely terminated; It has been observed that it is possible for patients to remain in long-term molecular remission without the use of TKI. Based on these studies, we will try to present the follow-up processes of chronic phase CML patients, who were followed up in our clinic and whose TKI treatment was stopped. First case; A 69-year-old female patient was diagnosed with Ph positive chronic phase CML in 2008. The imatinib treatment of the patient, who had been using imatinib for about 13 years and was bcr-abl negative for the last 3 years, was discontinued in December 2021. In the 2nd and 4th months, the requested bcr-abl was negative. Second case; a 42-year-old male patient was diagnosed with Ph-positive chronic phase CML in 2006. The patient, who had been using imatinib for about 16 years and was bcr-abl negative for the last 3 years, was discontinued in April 2022. bcr-abl came back negative. Third case; a 42-year-old female patient was diagnosed with Ph positive (IS: 31,824) chronic phase CML in 2019. He received Nilotinib and Dasatinib treatment after he had an allergic skin reaction using imatinib for about 2 years. The patient had drug intolerance and was bcr-abl negative for about 2 years, and the treatment was stopped. The 1-month follow-up was negative for bcr-abl. Fourth case; Imatinib was started in a 50-year-old female patient with the diagnosis of Ph-positive chronic phase CML in 2012. Due to imatinib intolerance, the treatment of the patient who was using nilotinib and was bcr-abl negative for the last 3 years was discontinued in February 2021. The bcr-abl negativity continues in the follow-ups. Fifth case: A 58-year-old female patient was diagnosed with Ph-positive chronic phase CML in 2013. The imatinib treatment of the patient, who has been using imatinib for about 8 years and has been negative for bcr-abl for the last 3 years, was discontinued in November 2021. The bcr-abl negativity continues in the follow-ups. STIM 1(Stop Imatinib) study is the first multicenter, non-randomised, prospective study on TKI termination.Then, TWISTER, A-STIM, ENEST, STOP2GTKI, EURO SKI studies were carried out.In these studies, TKI treatment was discontinued in patients who used TKI for at least 3 years and had a major molecular response for the last 2 years. Remission was achieved in approximately 50% of the patients who were followed up without medication. In our study; The treatment of patients who had been using TKI for 5 years and had a major molecular response for about 2 years was stopped. The follow-up of the patients (minimum: 1 month, maximum: 15 months) continues, and all of them are in remission.

First-in-human study of WT1 recombinant protein vaccination in elderly patients with AML in remission: a single-center experience

Wilms’ tumor 1 (WT1) protein is highly immunogenic and overexpressed in acute myeloid leukemia (AML), consequently ranked as a promising target for novel immunotherapeutic strategies. Here we report our experience of a phase I/II clinical trial (NCT01051063) of a vaccination strategy based on WT1 recombinant protein (WT1-A10) together with vaccine adjuvant AS01B in five elderly AML patients (median age 69 years, range 63–75) receiving a total of 62 vaccinations (median 18, range 3–20) after standard chemotherapy. Clinical benefit was observed in three patients: one patient achieved measurable residual disease clearance during WT1 vaccination therapy, another patient maintained long-term molecular remission over 59 months after the first vaccination cycle. Interestingly, in one case, we observed a complete clonal switch at AML relapse with loss of WT1 expression, proposing suppression of the original AML clone by WT1-based vaccination therapy. Detected humoral and cellular CD4+ T cell immune responses point to efficient immune stimulation post-vaccination, complementing hints for induced conventional T cell infiltration into the bone marrow and a shift from senescent/exhausted to a more activated T cell profile. Overall, the vaccinations with WT1 recombinant protein had an acceptable safety profile and were thus well tolerated.To conclude, our data provide evidence of potential clinical efficacy of WT1 protein-based vaccination therapy in AML patients, warranting further investigations.

Allogenic stem cell transplantation in multiple myeloma: dead or alive and kicking?

Multiple myeloma (MM) accounts for about 1.8% of all cancers and slightly over 17% of hematologic malignancies. Despite improvements in outcomes in recent years, currently, there is still no cure for this disease. Although allogeneic stem cell transplantation (Allo-SCT) is a potentially curative treatment, given the armamentarium of highly effective therapeutic options and a pipeline of novel agents, many opinion leaders sustain that there is no longer a role for this approach. Of note, several studies that did not include novel agents reported long-term molecular remissions, and possibly a cure, in a subset of patients after reduced-intensity conditioning/nonmyeloablative (RIC/NM) Allo-SCT. However, there are no current data supporting upfront Allo-SCT. Prospective trials combining the so-called "graft-versus-myeloma" effect and new drugs are an unmet medical need in high-risk patients. Early relapse after first-line treatment, which identifies patients with poor prognosis independently of other prognostic factors, could become a clinical indication.

Long-Term Clinical and Molecular Remissions in Patients with Mantle Cell Lymphoma (MCL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Background:Long-term clinical and molecular remissions in patients with MCL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for remission duration over 5 years. So the curability of this disease remains an open question. Patients and methods:Altogether 61 patients with MCL were treated in our institution with ASCT from 1998 to April 2019 (50 1st-line ASCT, ten 2nd-line ASCT, one 3rd-line ASCT). The data were collected retrospectively in 29 and prospectively in 32 patients who participated in two clinical trials: the 1st-line therapy trials of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Dreyling M, Blood 2005] and the European Mantle Cell Lymphoma Network [Hermine O, Lancet 2016], respectively. The diagnosis was regularly approved by the reference pathology of the GLSG (W.K.). The induction therapy before 1st-line ASCT consisted of 6 courses CHOP (n=11), mostly combined with rituximab and followed by Dexa-BEAM, and 6 alternating courses of R-CHOP and R-DHAP (n=39), respectively. For the salvage treatment patients usually received three to four courses of the DHAP protocol or the ESHAP protocol, since 2001 also combined with rituximab.Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols in remission. High-dose protocols: 1) total body irradiation with cyclophosphamide or melphalan and cytarabin (n=32) or 2) BEAM (n=29). Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible (n=4). Since 09/2016 patients received a maintenance therapy with rituximab after ASCT (every 2 months, planned for 3 years, n=14). Further details are described in an earlier publication of our first 36 patients (Metzner B, Ann Hematol 2013). Response assessment was performed by careful clinical examination and by ultrasound, chest x-ray and partly CT at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 5 years; n = 18), peripheral blood was regularly tested twice a year for minimal residual disease (MRD) by quantitative t(11;14) or allel specific IGH RQ-PCR and/or IGH-consensus PCR.Calculations were done using IBM SPSS Statistics Version 25. Data were analysed as of 01 July 2019. Results:With a median follow-up of 5 years (range 0.1-20) 10-year overall survival, progression-free survival (PFS) and freedom from progression (FFP) after 1st-line ASCT were 54%, 46% and 52%, respectively, after 2nd-line ASCT 42%, 20%and 20%, with a significant difference for PFS (p=0.045) and FFP (p=0.014) between 1st-line and 2nd-line cohort.Further prognostic factors (like sex, age, MIPI, bone marrow involvement, remission grade at ASCT: CR vs. PR, type of HDT: TBI vs. BEAM…) seemed to be without relevance (considering the small subgroups). Only one clinical relapse occurred after 5 years following ASCT in 1stor 2ndremission, respectively (one patient 6 years after 1st-line ASCT and another patient 7 years after 2nd-line ASCT and subsequent radiotherapy). So far, 18 patients experienced long-term remissions of at least 5 years (median 9 years, from 5 to 16 years). Fifteen of 17 tested patients were MRD negative at last follow-up, the two MRD positive patients (positive at a low level below the quantitative measuring range) had no clinical signs of relapse at last follow-up. None of these 18 patients had received rituximab maintenance therapy. None showed clinical criteria of "smoldering mantle cell lymphoma" at induction therapy. Treatment-related mortality at 100 days after ASCT was 1.6% (pneumonitis following TBI). One patient developed a secondary invasive malignancy in remission after ASCT (acute myeloid leukemia 4 years following TBI). Conclusion: Sustained long-term clinical and molecular remissions up to 16 years can be achieved following ASCT (without rituximab maintenance therapy), indicating the potential curative impact of 1st-line ASCT in MCL. The 2nd-line ASCT was obviously less effective. Disclosures Dreyling: Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Acerta: Other: scientific advisory board; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding.

The First Switched Time of PML/RARα Fusion Gene in Patients with Acute Promyelocytic Leukemia and Its Clinical Significance

To investigate the first switched time of PML/RARα fusion gene in patients with acute promyelocytic leukemia (APL) and its clinical significance. sixty cases of newly diagnosed APL were enrolled in this study. They received standard remission induction, consolidation and maintenance treatments according to the clinical pathway for APL, and were followed up. During the same time the PML/RARα fusion gene mRNA expression of all cases was detected by multi-nested PCR. except for 3 death cases and 1 case failed to follow-up, the PML/RARα fusion genes in the remaining 56 cases were firstly found to be negative from 24 to 381 days respectively, the mean value of the first switched time was 131 ± 90 days. There was no statistically significant difference in age, sex and risk stratification between different groups. However, the cases with L-type PML/RARα gene had shorter time compared with the patients with S-type PML/RARα gene (P = 0.032); then, for the above-mentimed 56 cases, the follow-up duration ranged from 25-1979 days (median 946 days), long-term molecular remissions had been observed in most cases, but 1 case with the first switched time of 133 days unfortunately recurred to be positive and followed by clinical relapse. The PML/RARα fusion gene in newly diagnosed APL patients was first switched to be negative in about 4 months after treatment. The first switched time of PML/RARα fusion gene can objectively reflect the reduction of leukemia cells, and the differences among different subtypes of PML/RARα fusion gene may have some suggestions for the treatment, but without important significance for the evaluation of prognosis and recurrence for APL patients. In addition, minimal residual disease (MRD) can be dynamically monitored by detecting PML/RARα fusion gene, thus having an important clinical significance for analysis of APL recurrence.

P4.06 - Long-term molecular remission with an increase of WT1-specific CTLs after cessation of WT1 peptide vaccination in a patient with CML

ABSTRACT Background: In order to clarify the safety and effectiveness of WT1 peptide vaccination for the patients with CML, we started WT1 peptide vaccination in combination with imatinib therapy for a patient with CML. Materials and Methods: A 51 years-old male with CML in CP had been treated with 400 mg imatinib for 2.5 years. Bcr-abl transcripts decreased transiently but gradually increased to more than 1, 000 copies thereafter. HLA-A*2402-restricted 9mer mutant WT1 peptides (CYTWNQMNL; a.a. 235-243), which had been identified to possess an anti-tumor immunogenicity, were administered subcutaneously at the dose of 1 mg/day every 2 weeks in combination with 400 mg imatinib for first 5 months and thereafter every 4 weeks for 12 months. The vaccination was undertaken 22 times totally. The appearance of WT1-specific CTLs in PB was confirmed by evaluating the frequency of MHC/WT1 tetramer + CD8+ T cells by using mixed lymphocyte peptide culture (MLPC). Results: Although bcr-abl transcripts increased up to more than 2,000 copies after the the initiation of WT1 vaccination every 2 weeks, the transcripts have decreased to less than 500 copies by the administration of WT1 peptides every 4 weeks. After seven months from the cessation of WT1 peptide vaccination bcr-abl transcripts decreased to the level of major molecular response (MMR), which is lasting thereafter for nearly 4 years. While WT1-specific CTLs were not detected in PB before WT1 peptide vaccination, the CTLs appeared after the second vaccination and remained at the level of nearly 15/106 CD8+ cells thereafter. The MHC/WT1 tetramer+ cells showed cytotoxicity against only leukemia cells expressing WT1 and HLA-A*2402. Conclusions: The present study showed that WT1 peptide vaccination for an imatinib-pretreated CML patient is feasible and effective, which is due to the long-lasting amplification of WT1-specific CTLs with cytotoxicity against WT1-expressing leukemia cells.

Long-term clinical and molecular remissions in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation

Long-term clinical and molecular remissions in patients with mantle cell lymphoma (MCL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Thirty-six patients with MCL received ASCT in our institution (27 patients undergoing first-line therapy, 8 patients undergoing second-line therapy, and 1 patient undergoing third-line therapy). In the case of long-term remission (≥5years; n = 8), peripheral blood was tested for minimal residual disease (MRD) by t(11; 14) polymerase chain reaction (PCR) and immunoglobulin heavy-chain (IGH) PCR at the last follow-up. Ten-year overall survival (OS), progression-free survival (PFS), and freedom from progression (FFP) after first-line ASCT were 42%, 43%, and 54%; after second-line ASCT, these were all 0%. Four-year OS, PFS, and FFP for the first-line cohort were 75%, 48%, and 61%, respectively. Four-year OS, PFS, and FFP after second-line ASCT were 55%, 30%, and 30%, respectively. Treatment-related mortality (3months after ASCT) was 0%. The only prognostic factor for OS, PFS, and FFP was treatment line (p = 0.011, p = 0.046, and p = 0.023, respectively). No relapses occurred after 5years following ASCT. So far, eight patients developed sustained long-term clinical and molecular complete remissions of up to 14.6years following ASCT in the first treatment line. Sustained long-term clinical and molecular remissions can be achieved following ASCT in the first treatment line and apparently less frequent in the second treatment line.

Long-term molecular remission with persistence ofBCR-ABL1-specific cytotoxic T cells following imatinib withdrawal in an elderly patient with Philadelphia-positive ALL

Long-term molecular remission with persistence of<i>BCR-ABL1</i>-specific cytotoxic T cells following imatinib withdrawal in an elderly patient with Philadelphia-positive ALL

P-210 Azacitidine and DLI as salvage therapy for MDS or AML relapse after allo-SCT induces long-term molecular remissions and increases Tregs

P-210 Azacitidine and DLI as salvage therapy for MDS or AML relapse after allo-SCT induces long-term molecular remissions and increases Tregs

Long‐term molecular remission with lenalidomide treatment of relapsed chronic lymphocytic leukemia

Lenalidomide is effective against relapsed chronic lymphocytic leukemia (CLL). We report the first case of long-term molecular remission with continuous lenalidomide treatment in a young patient with CLL relapsed to multiple treatments. Minimal residual disease was assessed by nested polymerase chain reaction on bone marrow samples with patient-specific primers. A 20-yr-old patient with standard-risk CLL was treated with lenalidomide after multiple relapses and achieved a 4yr long complete molecular response with minimal toxicities. Published biologic data support that lenalidomide induces an immune-mediated control of CLL, and our case suggests that long-term treatment with lenalidomide is effective at a molecular level in patients with relapsed CLL.

Recurrent CEP85L–PDGFRB fusion in patient with t(5;6) and imatinib-responsive myeloproliferative neoplasm with eosinophilia

Fusion genes involving the catalytic domain of tyrosine kinases (TKs) play an important role in the pathogenesis of hematological malignancies and solid tumors. In BCR–ABL1-negative myeloproliferative neoplasms (MPNs) several different tyrosine kinase fusion events have been described, most commonly involving the genes encoding the platelet-derived growth factor receptor alpha (PDGFRA) or beta (PDGFRB). Since the introduction of small molecule kinase inhibitors, TK fusions have emerged as prime therapeutic targets. Here, we report a recurrent CEP85L–PDGFRB fusion in a patient with eosinophilia and an MPN. The fusion was confirmed by specific amplification of the genomic breakpoints and reverse transcription polymerase chain reaction (PCR). The patient was treated with imatinib and achieved hematologic and cytogenetic remission. Minimal residual disease screening over 3 years with nested PCR failed to detect CEP85L–PDGFRB mRNA or genomic DNA, confirming a long-term molecular remission on imatinib.

Late Relapse of Acute Promyelocytic Leukemia: Literature Review and Results of Seven Years of Clinical and Laboratory Follow-Up of a Korean Patient

Among patients with acute promyelocytic leukemia (APL), 10% to 30% experience relapse. Most relapses occur within 2 years; only a few, known as late relapses, occur 4 years after achievement of the first complete remission (CR). We present a rare case of an ethnic Asian patient with APL who experienced late relapse, which has been continuously monitored by reverse transcription polymerase chain reaction (RT-PCR) for long-term molecular remission. Recently, the European APL Group published 2 large-scale studies related to laterelapse APL; however, only 2 Asian cases of late-relapse APL had previously been documented in the literature. We consider this case to be the first report of a patient with late-relapse APL in South Korea and believe that future studies of late-relapse APL for Asian and other ethnic groups are necessary.

Durability of complete remission by moxetumomab pasudotox (HA22 or CAT-8015) assessed by clone-specific real-time quantitative PCR (RQ-PCR).

2503^ Background: The anti-CD22 recombinant immunotoxin moxetumomab pasudotox, also known as HA22 or CAT-8015, was recently reported in phase I testing to achieve complete remissions (CRs) in 13 (46%) of 28 patients with relapsed/refractory hairy cell leukemia (HCL); 3 of 13 patients have relapsed. Methods: To complete this trial, 20 additional patients received the highest dose level (50 µg/Kg every other day x 3 doses); none of the 48 HCL patients had dose-limiting toxicity (DLT). Results: Of the first 42 patients with &gt;6 mo of follow up off-treatment, 23 (55%) had CRs, with an overall response rate of 88%. Of the 23 CRs, 21 were evaluable for minimal residual disease (MRD) using flow cytometry of blood and immunohistochemistry of the bone marrow biopsy, and 17 (81%) were negative. Of these 17 patients, 11 (65%) were negative by bone marrow aspirate (BMA) flow cytometry. PCR using consensus primers for the heavy chain immunoglobulin (IgH) rearrangement was less specific than flow cytometry of blood, since IgH rearrangements of normal B cells, which recovered rapidly after immunotoxin treatment, were also amplified. For better MRD detection in blood, patient IgH sequences were cloned and sequence specific primers and probes designed for real-time quantitative PCR (RQ-PCR). RQ-PCR of blood was negative in 6 (100%) of 6 patients achieving flow-negativity in both blood and BMA and positive in 3 (100%) of 3 patients flow-negative in blood but not BMA (p=0.01). No relapses from CR have been observed in 10 patients who became RQ-PCR-negative in blood or flow-negative in BMA, with 5-38 (median 11) mo of follow-up. Conclusions: We conclude that clone-specific RQ-PCR is the most sensitive blood test for MRD in our HCL patients after moxetumomab pasudotox, and could be used to assess the possibility of long-term molecular remissions. We believe these results, including durable CRs without DLT, support a pivotal trial in which moxetumomab pasudotox is compared with alternative therapy. Note: this summary contains investigator reported data. This study was funded by MedImmune, LLC, and supported by NCI’s Intramural Research Program and the Hairy Cell Leukemia Research Foundation.

Long-term seventh molecular remission in acute promyelocytic leukaemia

Long-term seventh molecular remission in acute promyelocytic leukaemia

Interferon Alpha 2a (IFN) Maintenance Therapy After Imatinib Plus IFN Induction Therapy in Chronic Myeloid Leukemia (CML) Induces Stable Long-Term Molecular Remissions and Is Associated with Increased Proteinase 3 (PR3) Expression and the Presence of PR1-Specific T-Cells.

Abstract 647Imatinib is a selective and very potent inhibitor of the BCR/ABL kinase. It induces ongoing complete cytogenetic remissions in the vast majority of chronic phase CML patients. However, BCR/ABL persistence is the rule despite ongoing imatinib therapy. This suggests that imatinib will not to cure CML and raises concerns about emerging imatinib resistance, long-term imatinib tolerability and compliance to therapy. We previously suggested that a combination of imatinib and immunotherapy by IFN may additionally control CML via induction of autologous cytotoxic T-cell (CTL) responses, such as those directed against the leukemia-associated antigen proteinase 3 (PR3). For example, induction of PR1-CTL which recognize PR3 on CML blasts was previously shown to be associated with IFN-, but not imatinib response. Indeed, we could recently demonstrate on a cohort of 20 newly diagnosed CML patients that low dose of IFN maintenance therapy alone was able to maintain or improve remissions obtained by a prior imatinib/IFN combination treatment (A. Hochhaus et al. , ASH 2007). After a median time of IFN maintenance therapy of 1.2 years 80% of the patients remained or improved molecular remission. Here we report a significantly longer follow up of these patients and translational studies to examine markers of IFN response. Twenty pts (14 m, 6 f; median age 45, range 23-74 yrs) with low (n=13), intermediate (n=6), and high risk (n=1) according to the Hasford score risk calculation have been investigated. Imatinib therapy had been administered for 2.4 yrs (0.2-4.9), combined with PEG-IFNa2a (Pegasys®, n=17) or IFN a2a (Roferon®, n=3). Maintenance therapy consisted of PEG-IFN (n=16) or IFN (n=4). Dose was adjusted according to response and tolerability and ranged between 135 μg PEG-IFN every 3 weeks to 180 μg PEG-IFN every week, or alternatively 2 to 5 * 3 Mill IU IFN/week. Imatinib was terminated due to side effects (n=5) or upon personal request of the patients after informed consent (n=15). At the time of imatinib withdrawal, two pts were in complete molecular remission (CMR) and 15 pts in major molecular remission (MMR). After a median observation time of 2.8 yrs (range 0.5-4.5), 15 pts were in MMR, 5 of them in CMR. Thus, the number of MMR patients increased from 2 at baseline to 5 after two years. Five patients relapsed within 0.4 years (range, 0.2-0.8) after imatinib discontinuation, but were rescued with imatinib, re-establishing molecular remission. Side effects to maintenance IFN were minor. We also studied putative markers of IFN response. IFN therapy was associated with an increase in the expression of PR3, and in the presence of auto-reactive PR1-CTL. PR1-CTL frequencies were prospectively assessed without prior in vitro amplification. In one of five assessable patients PR1-CTL were detected prior to imatinib withdrawal, but in four of seven assessable patients during IFN maintenance therapy. Longitudinal measurements of PR-1 CTL counts suggested an inhibition of the expansion of PR1-CTL by imatinib, implying that an optimal CTL expansion may occur preferentially in the absence of imatinib. This would explain the conversion to a CMR status in some patients only after imatinib withdrawal. Together, IFN maintenance after a prior imatinib/IFN induction therapy may be an effective alternative to permanent imatinib therapy, because it enables to safely discontinue imatinib even in those patients that have not achieved a CMR at the time of pausing imatinib. Induction of a PR1-specific CTL response by IFN may contribute to the particular efficacy of IFN after CML-debulking by imatinib. Disclosures:Burchert:Roche: Research Funding. Off Label Use: Pegasys(R) therapy in CML. Neubauer:Roche: Research Funding. Hochhaus:Roche, Novartis: Research Funding.

Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma

We enrolled 23 patients with relapsed follicular lymphoma (FL) in a prospective single-arm study of auto-SCT combined with in vivo rituximab graft purging and post transplant rituximab maintenance. Minimal residual disease was monitored with quantitative PCR testing. With a median follow-up of 74.2 months, neither median overall survival (OS) nor PFS has been reached. Here, 5-year OS and 5-year PFS are 78% (95% confidence interval (CI) 61-95%) and 59% (95% CI 38-80%), respectively. Time to progression (TTP) with the experimental regimen was significantly improved compared with TTP with the last prior treatment (P<0.001). Durable molecular remissions occurred in 11 of 13 assessable patients. PFS was significantly longer in patients who achieved a molecular remission by 3 months post-auto-SCT (P=0.001). Prolonged hypogammaglobulinemia occurred in most patients; however, no increase in major infections was observed.

Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: A randomized phase II study from the Nordic Lymphoma Group

The purpose of this phase II randomized trial was to evaluate the effect and safety of interferon-α2a (IFN) in combination with extended dosing rituximab in patients with symptomatic, advanced indolent lymphoma responding to a standard single course of rituximab. Totally 123 patients were treated with rituximab 375 mg/m2 once weekly for 4 weeks leading to 14 complete response (CR; 11%), 56 partial response (PR; 46%), and 13 minor responses (MR; 11%). Patients achieving either PR or MR were randomized to four more infusions of rituximab alone (n = 36) or in combination with five weeks of IFN (n = 33), with an overall response rate (CR + PR) of 78% and 94%, respectively. Significantly more patients in the combination arm improved their response from PR/MR to CR (P < 0.05) and more maintained their responses for ≥24 months (72% versus 50%), respectively. Overall, 26 out of the 52 patients who achieved CR underwent minimal residual disease (MRD) evaluation. Totally 17 of these (65%) achieved MRD negativity, 14 of whom remain in CR after 4.8 years' follow-up. The addition of IFN to rituximab was generally safe, but reversible thrombocytopenia and neutropenia were noted in one and six patients, respectively, requiring a reduction in the IFN dose. Extended rituximab is effective and well tolerated and combination with IFN seems to improve both the quality and duration of the responses, providing the opportunity to achieve long-term molecular CRs and prolonged failure-free survival without chemotherapy.

Unrelated donor haematopoietic cell transplantation after non‐myeloablative conditioning for patients with high‐risk multiple myeloma

Allografting induces long-term molecular remissions and possibly cure in myeloma patients. The development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high-dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pretreated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning consisted of fludarabine 90 mg/m(2) and 2 Gy total body irradiation. Graft-vs.-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. All patients except two (91%) readily engrafted. After a median follow-up of 20 (10-30) months, incidences of grade II-IV acute and extensive chronic GVHD were 50% and 61%. Overall response (OR) was 55%, with four (20%) complete and seven (35%) partial remissions. However, in patients allografted up-front OR was 89% whereas in the heavily pretreated group OR was 27% (P = 0.01). Two-year overall and event-free survivals were both 79% in the group transplanted up-front and 27% and 25% among relapsed patients (P = 0.025 and P = 0.006, respectively). Overall, six patients died of TRM and three of disease progression. Unrelated donor non-myeloablative allografting is feasible in myeloma. Disease control appears more pronounced when patients are treated soon after diagnosis.

Unrelated Donor Hematopoietic Cell Transplantation after Non-Myeloablative Conditioning for Patients with High Risk Multiple Myeloma.

Allografting can induce long-term molecular remissions and possibly cure in myeloma patients. The recent development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) typically associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pre-treated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at disease relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning regimen consisted of fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis included oral cyclosporine (CyA) and mycophenolate mofetil (MMF). CyA was administered at 6.25 mg/Kg every 12 hours from day -3; levels were targeted to the upper therapeutic range (450–500 ng/ml, Abbott TDX, Abbott Park, IL) for the first month post-transplant. In the absence of GVHD, CyA was tapered from day +100 and discontinued on day +177. MMF was administered from day 0 after PBSC infusion to day +40 at 15 mg/Kg every 8 hours, and then tapered till day +96. Twenty/22 (91%) patients readily engrafted. Two patients experienced graft failure and eventually recovered autologous hematopoiesis. After a median follow up of 11 months (3–27), TRM was 18% and 16/22 patients (73%) are alive. Deaths occurred in 10% of patients transplanted upfront and in 42% of those transplanted at relapse: 3 patients died from infections, 1 from hemolytic uremic/ thrombotic thrombocytopenic purpura syndrome, and 2 from disease progression (both were transplanted at relapse). Ten/20 engrafted patients (50%) had grade II–IV acute GVHD (10% grade III–IV), and 59% had extensive chronic GVHD. Overall response rate was 60% (including 20% CR): 78% in patients transplanted upfront (no disease progression observed) and 45% in those transplanted at relapse. In the two groups, progression-free and one year event-free survival were 100% and 44% (p<0.025), and 90% and 28% respectively (p<0.005).Unrelated donor non-myeloablative allografting is feasible with relatively low TRM and high response rate. Graft-versus-myeloma effect appears to be more efficient when patients are treated soon after diagnosis. Longer follow-up is needed to assess response duration.