Palifermin for oral mucositis after intensive therapy for hematologic cancers

BACKGROUND: Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability of palifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. METHODS: This double-blind study compared the effect of palifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 microg per kilogram of body weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation. RESULTS: The incidence of oral mucositis of World Health Organization (WHO) grade 3 or 4 was 63 percent in the palifermin group and 98 percent in the placebo group (P\u3c0.001). Among patients with this degree of mucositis, the median duration of mucositis was 6 days (range, 1 to 22) in the palifermin group and 9 days (range, 1 to 27) in the placebo group. Among all patients, regardless of the occurrence of mucositis, the median duration of oral mucositis of WHO grade 3 or 4 was 3 days (range, 0 to 22) in the palifermin group and 9 days (range, 0 to 27) in the placebo group (P\u3c0.001). As compared with placebo, palifermin was associated with significant reductions in the incidence of grade 4 oral mucositis (20 percent vs. 62 percent, P\u3c0.001), patient-reported soreness of the mouth and throat (area-under-the-curve score, 29.0 [range, 0 to 98] vs. 46.8 [range, 0 to 110]; P\u3c0.001), the use of opioid analgesics (median, 212 mg of morphine equivalents [range, 0 to 9418] vs. 535 mg of morphine equivalents [range, 0 to 9418], P\u3c0.001), and the incidence of use of total parenteral nutrition (31 percent vs. 55 percent, P\u3c0.001). Adverse events, mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration, were mild to moderate in severity and were transient. CONCLUSIONS: Palifermin reduced the duration and severity of oral mucositis after intensive chemotherapy and radiotherapy for hematologic cancers

Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers

BACKGROUND Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability ofpalifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. METHODS This double-blind study compared the effect ofpalifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 μg per kilogram ofbody weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation. RESULTS The incidence oforal mucositis of World Health Organization (WHO) grade 3 or 4 was 63 percent in the palifermin group and 98 percent in the placebo group (P<0.001). Among patients with this degree of mucositis, the median duration of mucositis was 6 days (range, 1 to 22) in the palifermin group and 9 days (range, 1 to 27) in the placebo group. Among all patients, regardless ofthe occurrence of mucositis, the median duration of oral mucositis of WHO grade 3 or 4 was 3 days (range, 0 to 22) in the palifermin group and 9 days (range, 0 to 27) in the placebo group (P<0.001). As compared with placebo, palifermin was associated with significant reductions in the incidence of grade 4 oral mucositis (20 percent vs. 62 percent, P<0.001), patient-reported soreness of the mouth and throat (area-under-the-curve score, 29.0 [range, 0 to 98] vs. 46.8 [range, 0 to 110]; P<0.001), the use ofopioid analgesics (median, 212 mg ofmorphine equivalents [range, 0 to 9418] vs. 535 mg of morphine equivalents [range, 0 to 9418], P<0.001), and the incidence of use of total parenteral nutrition (31 percent vs. 55 percent, P<0.001). Adverse events, mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration, were mild to moderate in severity and were transient CONCLUSIONS Palifermin reduced the duration and severity oforal mucositis after intensive chemotherapy and radiotherapy for hematologic cancers

Upfront transplantation for poor-risk aggressive non-hodgkin lymphoma and hodgkin’s disease: Who benefits?

High-dose therapy with autologous stem-cell transplantation is the standard treatment for patients with relapsed or primary refractory Hodgkin’s disease or non-Hodgkin lymphoma. The efficacy of the treatment in this setting has prompted extensive investigation of its role in upfront therapy for patients with a poor prognosis. Although the preliminary data appear promising, definitive results are still lacking, and upfront transplantation remains investigational. Newer regimens for the treatment of advanced-stage Hodgkin’s disease appear to confer cure rates of approximately 85% to 90%. Thus, only a small minority of patients may potentially benefit from more aggressive therapy such as upfront transplantation. A reliable method of identifying these patients is yet to be determined. Upfront transplantation should be evaluated in these patients once they are identified

Late Relapses Characterize Autologous Transplantation (ASCT) in First Complete Remission (CR) for Peripheral T-Cell Lymphoma (PTCL)

With the exception of ALK-positive anaplastic large cell lymphoma (ALCL), standard-dose chemotherapy is curative in a minority of patients (pts) with PTCL, and most pts have progressive disease less than 2 years from completing treatment. Several studies suggest that ASCT in 1st CR significantly improves the short-term outcome of pts with PTCL, but its long-term efficacy is not known. To address this, we assessed the outcome of sequential patients who underwent ASCT in 1st CR (n=15). Histologic subtypes were PTCL, unspecified, in 6 pts, angioimmunoblastic T-cell lymphoma in 5 pts, ALK-negative ALCL in 3 pts and hepatosplenic gamma delta T-cell lymphoma in 1 pt. Induction chemotherapy was CHOP (n=2) or CHOP-ICE hybrid (n=12) in 93% of pts. The age-adjusted IPI (AAIPI) was 2–3 in 9 of 14 assessable patients (64%), and 11 pts (73%) had stage III–IV disease. The conditioning regimen consisted of BEAM or CBV in 10 pts and TBI/Cy/VP-16 in 5 pts. All patients received peripheral blood progenitor cells for hematopoietic support. The median follow-up of all patients is 24 months (range 4.5–70). Five pts (33%) have progressed, with a median time to progression of 50 months (range 10–70). Four of the 5 pts who progressed did so more than 2 years from ASCT; they comprise 57% of patients with more than 2-years of follow-up. Four of 5 patients with progressive disease have died, with a median time from progression to death of 1 month (0.6–14.6). In this small series the AAIPI was not predictive of PFS or OS. While our results confirm the that ASCT in 1st CR significantly delays the time to progression, they suggest that it may not be curative in the majority of patients. If confirmed in ongoing larger prospective studies, this observation warrants trials of post-ASCT maintenance treatment and, for younger patients, trials of allogeneic transplantation in 1st CR or sequential ASCT followed by allogeneic transplantation. Figure Figur

The Importance of Molecular Phenotype in Predicting Overall Survival in Patients with Relapsed or Primary Refractory DLBCL Treated with Second-Line Chemotherapy and ASCT

Abstract From 1993–2001 we treated 186 patients (pts) with relapsed or primary refractory diffuse large B cell lymphoma (DLBCL) on IRB-approved clinical trials with ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy (SLT). Pts with chemosensitive disease received high dose chemoradiotherapy (HDT) and ASCT. In the context of these studies we reported the following: Pts achieving a complete response to ICE, pre-HDT/ASCT, have an improved overall survival (OS) (Journal of Clinical Oncology 1999, 12: 3776–85), pts with chemosensitive primary refractory disease have the same OS as relapsed pts (Blood 2000, 96: 2399–2404); and the second-line age-adjusted IPI (SAAIPI) predicts OS (Blood 2003, 102: 1989–96). In an attempt to further delineate prognostic factors in this setting tissue microarrays (TMA) were constructed as previously described by our group (Hum Pathol 2002: 968–74). All patients had a repeat biopsy prior to initiating SLT confirming active DLBCL; this sample was used for the TMA. Adequate tissue was available on 88 of these pts. TMA sections were stained for the following immunohistochemical markers and analyzed: MIB-1 (Ki-67), MUC1, MDR, p53, bcl-2, CD10, bcl-6, and MUM1. MIB-1 was scored in quartiles and for statistical purposes grouped as 1–2+ (50% tumor cells positive). For all other markers, a positive score was based on >20% of tumor cells staining positive. The "molecular phenotype"(MP), germinal center (GC) vs non-GC has an impact on progression-free survival in untreated DLBCL; we also evaluated whether the MP of the pre-ICE biopsy specimen could predict survival in pts with relapsed or primary refractory DLBCL undergoing SLT/HDT/ASCT. A GC phenotype is defined as either CD10 positive or bcl-6 positive and MUM 1 negative (Hans et al Blood2004; 103: 275–282). At a median follow-up of 6.5 years the the actuarial OS is 39.7% and 49% for patients receiving HDT/ASCT. In this subset of 88 pts, we confirmed that the SAAIPI predicted outcome: good risk pts having an OS of 52% and poor risk 26%, p<0.001 and pts with primary refractory disease that received HDT/ASCT had the same OS as those with relapsed disease. None of the TMA markers impacted outcome; nor was there a difference in outcome based upon GC vs. non-GC TMA MP. The OS of GC pts vs. non-GC pts as analyzed by intent to treat is 38.3% and 42.9% respectively, p=0.7; and for the pts who received HDT/ASCT (53.4% vs. 54.5%, p=.97) Conclusion: A non-GC "molecular phenotype" does not predict for a poor outcome in pts with relapsed or primary refractory DLBCL treated with ICE-based SLT followed by HDT/ASCT. MARKER ANALYSIS FOR 88 PTS WITH RELAPSED/REFRACTORY DLBCL MARKER OVERALL SURVIVAL P VALUE MIB 1 0–2+ 38.6% MIB 1 3–4+ 41% 0.9 MUC 1 neg. 39.2% MUC 1 pos. 40.6% 0.5 MDR neg. 34.5% MDR pos. 40.6% 0.6 p53 neg. 39.5% p53 pos. 41% 0.6 Bcl-2 neg. 37.1% Bcl-2 pos. 42.2% 0.9 CD10 pos. 39.7% CD10 neg. 40% 0.8 bcl-6 pos. 33% bcl-6 neg. 44% 0.5 MUM 1 neg. 36% MUM 1 pos. 41.8% 0.

Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma

To identify prognostic factors for patients transplanted for relapsed or refractory Hodgkin lymphoma we carried out a combined analysis of patients followed prospectively on 3 consecutive protocols at Memorial Sloan-Kettering Cancer Center. One hundred fifty-three patients with chemosensitive disease after ICE (ifosfamide, carboplatin, and etoposide)–based salvage therapy (ST) proceeded to high-dose chemoradiotherapy followed by autologous stem cell transplantation (ASCT). Patients were evaluated with computed tomography and functional imaging (gallium or fluorodeoxyglucose-positron emission tomography) prior to ST and again before ASCT. Functional imaging status before ASCT was the only factor significant for event-free survival (EFS) and overall survival by multivariate analysis and clearly identifies poor risk patients (5-year EFS 31% and 75% for FI-positive and negative patients respectively). Administration of involved-field radiotherapy with ASCT was marginally significant for EFS ( P = .055). Studies evaluating novel STs, conditioning regimens, post-ASCT maintenance, or allogeneic stem cell transplantation are warranted for patients who fail to normalize pre-ASCT functional imaging

Pre-Transplant Evaluation with Both CT and PET Following Second-Line Therapy Is Essential for Predicting Outcome in Patients with Transplant- Eligible Relapsed and Primary Refractory Hodgkin Lymphoma

Abstract The standard treatment for relapsed and primary refractory (rel/ref) Hodgkin lymphoma (HL) for patients (pts) who demonstrate chemosensitivity to second-line chemotherapy (ST) is high dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT). Since 1994, four studies at our institution evaluated ICE (ifosfamide, carboplatin, and etoposide) based salvage therapy followed by HDT-ASCT in rel/ref HL. Chemosensitivity is a requirement for pts to proceed to HDT-ASCT, however the definition of chemosensitivity is broad. We use both functional imaging (gallium or PET) and CT to assess response to ICE; pts with chemosensitive disease fall into three groups: normalization of CT and FI (NRM), residual mass on CT but with negative FI (RM, FI-), and FI positivity regardless of CT finding (FI+). Here we report the outcome for pts who responded to ICE ST and proceeded to HDT-ASCT. Between October 1994 and February 2008, 198 pts received ICE on 1 of 4 consecutive protocols (169 pts) or as per protocol (29 pts) and were deemed transplant-eligible. The median follow-up for surviving patients is 7.4 years. There were 99 male pts and 99 female pts; the median age was 31. With respect to the 3 pre-salvage chemotherapy risk factors (RF) (relapse within 1 year of primary treatment, presence of extranodal disease, and B symptoms): 44 pts had 0 RF, 64 had 1 RF, 75 had 2 RF, and 8 had 3 RF. Bulky disease defined as greater than 5cm or 10cm was present in 60 (30%) and 15 (7.5%) pts respectively. The five year event free survival (EFS) and overall survival (OS) were 69% and 78% respectively. Seventy six (38%) had a NRM response to ST, 73 (37%) had a RM, FI- response, and 49 (25%) were FI+. The 5 year EFS and OS for the three groups were 86% and 93%, 71% and 79%, and 41% and 51% respectively. There was a statistically significant improvement in OS and EFS for the NRM and RM, FI- groups compared to the FI+ group (p<0.0001). Surprisingly, a comparison between the NRM and RM, FI- groups also revealed a statistically significant improvement in EFS and OS for the NRM group (p=0.05 and 0.04 respectively). Response to ICE ST followed by HDT-ASCT is associated with a prolonged EFS and OS. The quality of response to ICE ST had a significant impact on outcome. Both a residual mass with normalized FI and abnormal FI after ST predicts for an inferior outcome following HDT-ASCT. However, residual radiotracer on FI was associated with the poorest outcome in both EFS and OS. CONCLUSION: Outcome cannot be predicted by FI alone since both RM, FI- and FI+ groups had an inferior outcome compared to NRM. The most accurate post treatment evaluation includes both CT and PET. Figure Figur

Second-Line Therapy with ICE Followed by High Dose Therapy and Autologous Stem Cell Transplantation for Relapsed/Refractory Peripheral T-Cell Lymphomas: Minimal Benefit When Analyzed by Intent To Treat

Abstract Background: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin’s lymphomas with a poorer prognosis than their B-cell counterparts. Second -line chemotherapy (SLT) followed by high dose therapy and autologous stem cell transplantation (HDT/ASCT) is a common approach to patients (pts) with relapsed PTCL. Reports evaluating this approach have analyzed the outcome of transplanted patients. Our goal was to identify pts with relapsed or refractory disease, treated in a uniform manner, with the intent to induce a remission and proceed to HDT/ASCT. Patients and Methods: From our ICE database we identified 40 pts with a diagnosis of a mature T or NK lymphoma who received ICE as SLT therapy prior to planned HDT/ASCT. Histologic subtypes were as follows: PTCL NOS (n=15), anaplastic large cell lymphoma (n=11), angioimmunoblastic T-cell lymphoma (n=5), NK/T cell lymphoma (n=4), subcutaneous panniculitis-like T-cell lymphoma (n=2), and one each of hepatosplenic γ/δ T-cell lymphoma, enteropathy associated T-cell lymphoma, and transformed mycosis fungoides. Median age was 48 years (24–73), five pts were ≥ 60 years. Twenty-five men and 15 women were treated. Initial chemotherapy regimens included: CHOP/CHOP-like (n=32), NHL-15 (n=5), and other (n=4). Twenty-two pts responded to their initial therapy and 18 had primary refractory disease. At time of relapse, 24 pts had stage IV disease, 23 had elevated LDH, and 9 had a performance status ≤ 70%. Thirty-one pts had at least one extranodal site. Complete second line International Prognostic Index (IPI) factors (AA stage, LDH, PS) were available for 36 pts. IPI scores were LR (n=3), LIR (n=12), HIR (n=13), and HR (n=8). Results: All pts received at least one cycle of ICE, 36 received all three planned cycles. Fourteen patients (35%) achieved a complete response, 14 (35%) had a partial response, four (10%) had stable disease, and eight (20%) progressed on therapy. Twenty-seven (68%) pts went on to receive HDT/ASCT. Median follow-up for surviving pts was 45 months (range 7–104). By 3 years, 33/40 (83%) of pts had relapsed with a median progression free survival (PFS) of 6 months from last ICE treatment. Twenty-eight (70%) pts relapsed within 1 year. Neither second-line IPI nor histologic subtype was predictive of continuous remission. Relapsed pts had a superior 3 year PFS compared to primary refractory pts 20% vs 6% (p=0.0005). Despite high relapse rate, 18/40 (45%) of pts were alive at last follow-up. Conclusion: SLT and HDT/ASCT is a common treatment strategy for pts with relapsed PTCL. However, when examined by intention to treat from initiation of SLT and not from time of transplant few pts have durable benefit from this approach. Despite the high response rate to SLT, consolidation with HDT/ASCT provides little clinically meaningful benefit for most pts. The number of pts alive with other therapies despite early relapse underscores the need to study alternative or maintenance strategies for those who achieve remissions