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Survival and late effects in children with Hodgkin's lymphoma treated with MOPP/ABV and low-dose, extended-field irradiation.

PURPOSE: Reduced-intensity protocols for pediatric Hodgkin's lymphoma are aimed at preserving excellent relapse-free survival while decreasing the incidence of late effects. PATIENTS AND METHODS: We retrospectively reviewed the outcome of 123 children treated consecutively for Hodgkin's lymphoma at a single institution. Patients with stages I-IIIB disease received three cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/ doxorubicin, bleomycin, and vinblastine (ABV) followed by 15 Gy of extended-field irradiation, while those with stage IV disease were treated with six to eight cycles of MOPP/ABV chemotherapy with or without radiotherapy. RESULTS: At a median follow-up of 8.5 years (range, 1.4 to 15.5 years), the estimated 10-year overall survival and event-free survival are 94% (SE, 2.2%) and 88% (SE, 3.1%) respectively. There have been 12 treatment failures and six disease-related deaths. A very large mediastinal mass ( 50% of the maximal thoracic diameter) was associated with a 10-year event-free survival of 50% (SE, 14%) compared with 91% (SE, 4.0%) for smaller masses (P < .001). Late cardiopulmonary toxicity is largely absent, and the incidence of hypothyroidism is 14%. There have been no cases of secondary leukemia and four secondary solid malignancies observed to date. CONCLUSION: MOPP/ABV and low-dose, extended-field radiotherapy is an effective treatment for pediatric Hodgkin's lymphoma. With median follow-up of 8.5 years, late cardiopulmonary effects and secondary malignancies from this treatment regimen are infrequent. Continued longitudinal observations, particularly for breast cancer in female patients and gonadotoxicity, will determine whether the goal of decreasing treatment-related complications while maintaining excellent survival has been achieved.

Adolescent↗

Topographic variations in the clonogenic response of intestinal crypts to cytotoxic treatments.

In the intestinal crypt microcolony assay, a "surviving fraction" of whole crypts is calculated conventionally by dividing the number of regenerating crypts three to four days after treatment by the number of crypts in untreated animals, both measured around a complete intestinal circumference in transverse sections of gut. We show that in relation to the mesenteric attachment of the gut, crypts in different regions of this circumference differ in their survival characteristics after radiation or mechlorethamine hydrochloride ("HN2"). Crypts associated with Peyer's patches are resistant to both agents (large initial shoulder, shallow slope). The mode of administration of HN2 (IP vs. IV) influences the shape of the crypt survival curve. Differences in size of shoulder and slope affect the estimate of numbers of microcolony-forming cells per crypt (A). For radiation, this number can vary sevenfold, depending on the region of circumference chosen for analysis. Different agents of assay result in radically different values for A.

Animals↗

Effect of nitrogen mustard, a vesicant agent, on lymphocyte energy metabolism.

BACKGROUND: The vesicant agents sulfur and nitrogen mustards, which contain chloroethyl groups, are potent inhibitors of DNA synthesis and cell growth, likely changing the utilization of anaerobic glycolysis for energy generation. METHODS: To investigate the effect of nitrogen mustard on cellular energy metabolism, lymphocytes treated with increasing doses of mechlorethamine (HN2), a nitrogen mustard and an analogue of sulfur mustard, were incubated with radiolabeled glucose. The rates of aerobic and anaerobic glycolysis were then determined. RESULTS: Glycogen consumption was significantly higher in cells treated with HN2 in a dose-dependent manner compared to untreated cells. Similarly, the amount of end-product lactate was increased, but CO2 was reduced in HN2-treated cells. CONCLUSIONS: Lymphocytes normally use aerobic glycolysis under aerobic conditions, but energy metabolism predominantly involved anaerobic glycolysis after severe intoxication with mustard agent.

Adult↗

MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989-2000).

The purpose of this retrospective study was to evaluate the efficacy and toxicity of the MOPP chemotherapy protocol (mechlorethamine, vincristine, procarbazine, and prednisone) as a rescue regimen in dogs with lymphoma. One hundred seventeen dogs that had resistance to previously administered chemotherapy were evaluated. Before treatment with MOPP, all dogs received a median of 6 chemotherapy drugs for a median duration of 213 days. Thirty-one percent (36 of 117) had a complete response (CR) to MOPP for a median of 63 days, and 34% (40 of 117) had a partial response (PR) for a median of 47 days. Sixteen percent (19 of 117) had stable disease (SD) for a median of 33 days. Predictors for response to MOPP were not identified. Gastrointestinal (GI) toxicity occurred in 28% (33 of 117) of the dogs, and 13% (15 dogs) required hospitalization. Five dogs developed septicemia, and 2 died as a result. MOPP was an effective treatment for dogs with resistant lymphoma and was well tolerated by the majority of affected dogs.

Animals↗

Treatment of cutaneous T cell lymphoma: current status and future directions.

The treatment of cutaneous T cell lymphoma (CTCL), which includes mycosis fungoides and Sezary syndrome, has been in a state of continual change over recent decades, as new therapies are constantly emerging in the search for more effective treatments for the disease. However, prognosis and survival of patients with CTCL remains dependent upon overall clinical stage (stage IA-IVB) at presentation, as well as response to therapy. Past therapies have been limited by toxicity or the lack of consistently durable responses, and few treatments have been shown to actually alter survival, especially in the late stages of disease. Even aggressive chemotherapy has not been shown to improve overall survival compared to conservative sequential therapy in advanced disease, and adds the risk of immunosuppressive complications. Over the last decade, extracorporeal photopheresis has been the only single treatment that has been shown to improve survival in patients with Sezary syndrome, although its true efficacy and place in combination therapy remain unclear. Much of the focus of current research has been on combinations of skin-directed therapies and biological response modifiers, which improve response rates. The results of various trials over the years have also brought into favor the use of post-remission maintenance therapy with topical corticosteroids, topical mechlorethamine (nitrogen mustard), interferon-alpha, or phototherapy to prevent disease relapse. Recent novel developments in CTCL therapy include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL, and the topical gel formulation of bexarotene, which plays a role in treating localized lesions. US Food and Drug Administration (FDA)-approved, oral systemic bexarotene has the advantage of a 48% overall response rate at a dosage of 300 mg/m(2)/day, and avoids immunosuppression and risk of central line and catheter-related infectious complications that are associated with other systemic therapies. Monitoring of triglycerides and use of concomitant lipid-lowering agents and thyroid replacement is required in most patients. Also recently FDA-approved, denileukin diftitox is the first of a novel class of fusion toxin proteins and is selective for interleukin-2R (CD25+) T cells, targeting the malignant T cell clones in CTCL. Denileukin diftitox is associated with capillary leak syndrome in 20 to 30% of patients, which may be ameliorated by hydration and corticosteroids. Higher response rates are possible by combining bexarotene with "statin" drugs and active CTCL therapies. Studies are being conducted on combining bexarotene and denileukin diftitox with other modalities. Biological response modifier therapies that are in current or future investigational trials include topical tazarotene, pegylated interferon, interleukin-2, and interleukin-12. At the forefront of systemic chemotherapy development, pegylated liposomal doxorubicin, gemcitabine, and pentostatin appear to have the greatest potential for success in CTCL therapy. Bone marrow transplantation, which is currently limited by the risk of graft-versus-host disease, offers the greatest potential for disease cure. Further developments for CTCL may include more selective immunomodulatory agents, vaccines, and monoclonal antibodies.

Adrenal Cortex Hormones↗

Assessment of cardiac and pulmonary function in adult patients with Hodgkin's disease treated with ABVD or MOPP/ABVD plus adjuvant low-dose mediastinal irradiation.

We evaluated the long-term effects of combined modality therapy (CMT) with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) or mechlorethamine, vincristine, prednisone, procarbazine (MOPP)/ABVD plus adjuvant low-dose (< 30 Gy) involved-field radiation therapy (LDRT) on cardiac and pulmonary functions in adult patients with Hodgkin's disease (HD). Adjuvant LDRT (mean dose, 2340 cGy) to the mediastinum was administered to 24 patients after chemotherapy with MOPP/ABVD (n = 10) and ABVD (n = 14). The mean doses of doxorubicin and bleomycin were 233 mg/m2 and 92 IU/m2, respectively. Cardiac and pulmonary function tests were performed in all patients and, when available, were compared with pretreatment studies. After a median follow-up of 6.3 years, none of the patients had cardiac or pulmonary symptoms. A 4.7% overall decrease in left ventricular ejection fraction (LVEF) was observed (p = 0.03), but only one patient had a mildly decreased LVEF (47%). Diastolic function, LVEF, and left ventricular volume remained within the normal range in the other 23 patients. Mild pulmonary function study abnormalities occurred in 8 of 24 patients, 6 of whom were cigarette smokers. There were no significant changes in total lung capacity and forced vital capacity (FVC) values, but there was a 3% overall decrease in FEV1/FVC ratio (p = 0.05). In adult patients with HD, adjuvant LDRT after chemotherapy with ABVD or MOPP/ABVD did not result in a significant incidence of permanent pulmonary or cardiac toxicity after more than 6.3 years of median follow-up. Further studies are warranted to fully evaluate the impact of such therapy on cardiopulmonary function.

Adolescent↗

Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustards.

The kinetics of formation and removal of DNA interstrand crosslinks (ISC), DNA-protein crosslinks (DPC), and single strand breaks (SSB) by several nitrogen mustards were compared in order to determine the degree to which lesion selectivity may vary. The kinetic measurements using DNA alkaline elution methodology were obtained in mouse L1210 cells treated with mechlorethamine (HN2), phenylalanine mustard (L-PAM), uracil mustard (UM), 6-methyl-UM, and quinacrine mustard (QM). The ISC or DPC challenge delivered to cells was gauged on the basis of the kinetics as either total ISC or DPC produced, or as the area under the lesions versus time curve (AUC). By either measure (excepting QM), ISC correlated well with loss of colony survival, whereas DPC did not. The ISC/DPC ratio may therefore be a useful index of lesion selectivity. This ratio was significantly greater for 6-methyl-UM than for HN2. The ratio was also greater for L-PAM than for HN2 but only when gauged by AUC; this was attributable to an unusually slow rate for ISC removal in the case of L-PAM. The preferential reaction of UM at some 5'-GC-3' sites in purified DNA had suggested that UM might produce ISC with increased efficacy. UM, however, was somewhat less efficacious in ISC production than was 6-methyl-UM, which lacked selectivity for alkylation at 5'-GC-3'. QM was the only compound that produced detectable SSB, and the SSB were so numerous that ISC could not be quantitated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Combination chemotherapy for advanced Hodgkin's disease after failure of MOPP: ABVD and B-CAVe.

Between 1973 and 1982, 110 patients with advanced Hodgkin's disease who had had disease progression while receiving MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy or a relapse after a MOPP-induced complete remission were treated with either ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (58 patients) or B-CAVe (bleomycin, lomustine, doxorubicin, and vinblastine) (52 patients) chemotherapy in concurrent nonrandomized trials. Responses were seen in 39 of 55 (71%) evaluable ABVD-treated patients--21 (38%) complete and 18 partial responses--and in 34 of 48 (71%) evaluable B-CAVe-treated patients--21 (44%) complete and 13 partial responses. The median duration of the ABVD-induced complete remissions is greater than 25 months compared with 24.3 months for B-CAVe-induced remissions. The 5-year actuarial freedom from progression is 8.5% for evaluable ABVD-treated patients and 25% for B-CAVe-treated patients (p = 0.10). Toxicity in the two treatment groups was similar, with only significant thrombocytopenia (platelet count, less than 50 000/mm3) being more common with B-CAVe. Although most patients with Hodgkin's disease refractory to MOPP treatment will respond to either ABVD or B-CAVe chemotherapy, subsequent long-term disease-free survival is unusual. The need for improved treatment programs for this patient group is evident.

Adolescent↗

BCVPP chemotherapy for advanced Hodgkin's disease: evidence for greater duration of complete remission, greater survival, and less toxicity than with a MOPP regimen. Results of the Eastern Cooperative Oncology Group study.

Two chemotherapy regimens for treatment of patients with advanced Hodgkin's disease, BCVPP (carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone) and MOPP (mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone), were compared in a randomized prospective study. Two hundred ninety-three patients were evaluable in the induction phase of this study. The complete remission rate with BCVPP was 76% (112/147) and with MOPP, 73% (106/146) (p = 0.51). The duration of complete remissions for previously untreated patients given BCVPP was significantly longer than that for previously untreated patients given MOPP (p = 0.02). Although hematologic toxicities were similar, BCVPP caused less gastrointestinal (p = 0.0001) and neurologic toxicity (p = 0.01) than MOPP. Previously untreated patients achieving complete remission with BCVPP survived significantly longer than those receiving MOPP (p = 0.03). As primary induction chemotherapy for advanced Hodgkin's disease, BCVPP is an effective alternative to MOPP, having equal or greater therapeutic benefit with less toxicity.

Adult↗

Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin's disease. A report of 8-year results.

In patients with stage IV Hodgkin's disease mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was randomly tested against MOPP alternated monthly with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). All 88 evaluable patients had not received chemotherapy and 25 had had a relapse after primary irradiation. The complete remission rate with MOPP/ABVD was 88.9% (40 of 45 patients), and with MOPP, 74.4% (32 of 43 patients). The 8-year results show that MOPP/ABVD was superior to MOPP in terms of freedom from progression (64.6% compared to 35.9%; p less than 0.005), relapse-free survival (72.6% compared to 45.1%; p less than 0.01), total survival (83.9% compared to 63.9%; p less than 0.06), and survival of complete responders (94.8% compared to 77.1%; p = 0.04). The delivery of MOPP/ABVD was not associated with an increased incidence of major toxicity. The early sequential rotation of two equally effective and non-cross-resistant drug combinations can substantially improve the likelihood of cure in patients with Hodgkin's disease.

Adolescent↗

Intercurrent death after Hodgkin disease therapy in radiotherapy and adjuvant MOPP trials.

STUDY OBJECTIVE: To assess long-term differences in mortality associated with initial Hodgkin disease therapy. DESIGN: Retrospective review of patients treated in prospectively randomized clinical trials. PATIENTS: Three hundred twenty-six patients with pathologic stage I, II, or III, A or B Hodgkin disease treated between 1967 and 1980 with median follow-up exceeding 14 years. INTERVENTIONS: Patients at the same stage of disease were randomized to receive radiation alone (167 patients) or radiation followed by 6 cycles of mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone (MOPP) chemotherapy (159 patients) with additional therapy for progression or recurrence. MEASUREMENTS AND MAIN RESULTS: No significant differences between treatment regimens for actuarial survival, intercurrent disease, or Hodgkin disease mortality were seen. Thirty-three patients who received radiation alone and 30 patients who received adjuvant chemotherapy died without evident Hodgkin disease. Death was caused by second neoplasms in 28 patients (relative risk, 2.35; 95% CI, 1.46 to 3.24). Six patients developed acute myelogenous leukemia or a myeloproliferative disorder after treatment including MOPP. Chemotherapy exposure varied among the 8 patients with lung cancers, 6 with gastrointestinal and 3 with other adenocarcinomas, 3 with sarcomas, 1 with diffuse large cell lymphoma, and 1 with melanoma. Acute myocardial infarction caused 9 of 17 cardiovascular disease deaths with 5 occurring in patients between the ages of 33 and 43. Nonetheless, the risk for acute myocardial infarction was not clearly increased (relative risk, 0.86; 95% CI, 0.42 to 1.57). Fifteen patients died from infection: 5, opportunistic; 5, asplenic sepsis; and 5, other pneumonias. Two patients died in accidents, and 1 died from radiation pneumonitis. CONCLUSIONS: Adjuvant MOPP chemotherapy improved freedom from relapse without significant survival benefit or impairment. Leukemogenesis was the only lethal complication associated with MOPP. Survivors of Hodgkin disease had an increased risk for death from a second neoplasm, but no apparent increased risk for death from acute myocardial infarction.

Actuarial Analysis↗

Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute.

The results of treatment of 198 patients with Hodgkin's disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkin's disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkin's disease appears to be curable by chemotherapy.

Adolescent↗

Persistent immunologic abnormalities in long-term survivors of advanced Hodgkin's disease.

Immunologic studies were done on 47 long-term survivors of Hodgkin's disease who had been treated with MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone). Percentages of E rosettes and mitogen-induced lymphocyte proliferation were significantly reduced compared to those in normal control subjects. There was no tendency for these abnormalities to return to the normal range with increasing disease-free intervals. No abnormalities of B-cell number or function were detected. Long-term survivors of advanced diffuse histiocytic lymphoma treated with comparable chemotherapy, who served as a control population, had significantly higher percentages of E rosettes and no reduction in mitogen-induced lymphocyte proliferation. Thus these persistent immunologic abnormalities cannot be attributed to chemotherapy alone. The presence of similar immunologic abnormalities in untreated patients with Hodgkin's disease of all stages and in patients cured by either MOPP or radiotherapy suggests that depressed cellular immunity may be an inherent characteristic of the person in whom Hodgkin's disease develops.

Adult↗

Salvage chemotherapy with ABVD in MOPP-resistant Hodgkin's disease.

Fifty-five consecutive patients with advanced recurrent Hodgkin's disease resistant to MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone) were given ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine). In 54 patients evaluable for response, complete remission after pathologic restaging was seen in 59% and partial remission in 13%. Fifteen of 29 patients (52%) showing disease progression during primary MOPP treatment achieved complete remission after ABVD. The median time to complete response was 3 months. The median duration for complete remission was 17 months, and 38% of patients who attained complete remission have remained alive and continuously disease free at 5 years from start of ABVD treatment. The median survival of complete responders was more than 60 months. Toxic manifestations were moderate, aside from pronounced vomiting in more than half of patients. These results indicate that ABVD is an effective salvage regimen for MOPP-resistant Hodgkin's disease.

Adolescent↗

Diffuse aggressive lymphomas: increased survival after alternating flexible sequences of proMACE and MOPP chemotherapy.

A new treatment program was developed in an attempt to increase the complete remission rate and survival of previously untreated patients with advanced stages of diffuse aggressive lymphomas. A flexible number of cycles of ProMACE chemotherapy (prednisone, methotrexate, doxorubicin, cyclophosphamide, and epipodophyllotoxin VP-16) was alternated with a flexible number of cycles of MOPP chemotherapy (mechlorethamine, vincristine sulfate, procarbazine, and prednisone), and finally late intensification with ProMACE therapy was given. The duration of each phase of treatment was determined by the patient's rate of tumor response. Complete remissions were achieved in 55 of 74 patients (74%) with a median duration of follow-up exceeding 2 1/2 years. Only ten of the complete responders (18%) have had relapse. The dose-limiting toxicity is myelosuppression, and eight patients (10%) died from sepsis. Median survival for all patients has not been reached but is predicted to exceed 4 years with 65% of patients alive at 4 years. Previously we achieved a 46% complete remission rate with 38% of all patients alive at 4 years; relapse-free survival beyond 2 years was tantamount to cure. Therefore, ProMACE-MOPP chemotherapy represents a substantial improvement in treating patients with diffuse aggressive lymphomas.

Adolescent↗

Safe, compact and portable system for regional chemotherapeutic hyperthermic perfusion procedures.

Perfusion techniques utilizing hyperthermic chemotherapy have been established as a successful modality of therapy for isolated metastatic malignant melanoma. The combination of chemotherapeutic agents (Dactinomycin, thiotepa and Mechlorethamine HCl) given in high doses, not possible systemically, combined with hyperthermia (40-42 degrees C) in an isolated extremity has shown greater tumor regression compared with systemic medication only. Many of the isolated limb perfusion procedures are performed in non-cardiac centers, especially at specialized cancer institutions. This often presents new obstacles for the perfusionist including lack of adequate perfusion equipment and disposables. Other obstacles include unfamiliarity of the operating room staff with the heart-lung machine and inappropriate and/or unsafe handling of the perfusion circuit. In order to overcome these obstacles and enhance safety, portability and effectiveness, the authors have developed an isolated limb perfusion system. The purpose of this study was to compare the parameters of treatment and long term outcomes demonstrated by our system and method, to previously published data. The qualitative comparative analysis was performed between eight treatments with this type of perfusion system and outcome data previously published. It is the authors' conclusion that the portable isolated limb perfusion system achieved all of the required parameters to provide safe and effective treatment for this type of melanoma. No demonstrated variation of the long term clinical results in our patient population was seen when compared to previously published data.

Adult↗

Molecular dynamics simulation of metallothionein-drug complexes.

The intermolecular interactions of metallothionein with nitrogen mustard drugs were studied by molecular dynamics simulations. Previous laboratory experiments have defined selective alkylation of two cysteine residues, and selective binding was proposed to precede alkylation. The present study provides information about accessibility to cysteines based on evaluating the intermolecular energies and distances in the first few ps of dynamics simulations. A series of dynamics simulations was performed with three drug molecules positioned at the eight most solvent accessible cysteine residues of the dimeric form of the protein. Sites proximal to the sulfhydryl groups of Cys-33 and Cys-48 were found to be the most favorable for complexing the aziridinium forms of chlorambucil, melphalan, and mechlorethamine. The sites for preferential binding are in qualitative agreement with the sites of selective alkylation defined experimentally.

Binding Sites↗

Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial response after six cycles of chemotherapy for patients with advanced Hodgkin's disease: results of the groupe d'études des lymphomes de l'Adulte H89 trial.

The treatment of advanced Hodgkin's disease (HD) with chemotherapy (CTx) alone or combined modality treatments has been controversial. In 1989, we designed a randomized study to compare 2 cycles of CTx to (sub)total nodal irradiation (RTx) as consolidation treatments for patients with stage IIIB/IV HD in complete remission (CR) or good partial response after 6 cycles of CTx. A total of 559 patients were randomized to receive 6 cycles of MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine) hybrid (n = 266) or ABVPP (n = 267). After induction treatment, 418 patients could be evaluated for the consolidation phase. With a median follow-up of 48 months, the 5-year disease-free survival estimates were 80% for 8 cycles of MOPP/ABV, 82% for 6 cycles of MOPP/ABV plus RTx, 68% for 8 cycles of ABVPP, and 75% for 6 cycles of ABVPP plus RTx (P =.01). The 5-year disease-free survival estimates did not differ between CTx and RTx, 74% and 79%, respectively (P =.07). After MOPP/ABV, the 5-year overall survival estimates did not differ between CTx and RTx, 85% and 88%, respectively (P =.2). After ABVPP, the 5-year survival estimates were 94% for CTx and 78% for RTx (P =.002). These results showed that RTx was not superior to CTx consolidation after doxorubicin-induced CR for patients with advanced HD. Because of the uncertainty of obtaining a prolonged second remission for patients relapsing after CTx and RTx and the possible long-term effects of RTx, we prefer 8 cycles of CTx as standard treatment when a CR has been achieved after 6 cycles.

Adolescent↗